Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
  • A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
  • A61J7/0015—Devices specially adapted for taking medicines
  • A61J7/0061—Swallow helping devices, e.g. tongue shields
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
  • A23P30/00—Shaping or working of foodstuffs characterised by the process or apparatus
  • A23P30/10—Moulding
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof

Definitions

• the present invention relates to the art of oral delivery of pharmaceutical and nutritional products and especially relates to a swallowing aid for use with distinct and intact solid dosage forms of pharmaceuticals and nutritional products to be administered orally.
• dysphagia i.e., difficulty in swallowing
• the prevalence of dysphagia (i.e., difficulty in swallowing) among non-treatment-seeking people older than 65 years is around 15% and becomes even higher (30%) in a population over 75 years (Roy, N. et ai, Ann Otol Rhinol Laryngol 2007, 1 16(1 1 ): 858-65, Chen, P.H. et ai, Dysphagia 2009, 24(1 ): 1 -6).
• the absolute number of people suffering from swallowing problems increases markedly, when patients of certain diseases are included and when all age groups are considered.
• the most common diseases causing swallowing problems are stroke (prevalence 15 million worldwide), chronic obstructive pulmonary disease (COPD; prevalence higher than 13 million in the USA), and Alzheimer's disease (prevalence 4 million in the USA).
• stroke prevalence 15 million worldwide
• COPD chronic obstructive pulmonary disease
• AD Alzheimer's disease
• the incidence of dysphagia is 80% (Ha, L. et al., Tidsskr Nor Laegeforen 2008, 128(17): 1946-50).
• the swallowing process is a complex reflex that requires perfect synchronization of the muscles implicated in swallowing and respiration (Logemann, J.A. et ai, Folia Phoniatrica Logopaedica 1998, 50(6):31 1 -319).
• the coordination of these muscles may be impaired even without any specific disease.
• symptoms of dry mouth are not infrequent. Therefore, dysphagia is not a problem experienced only by elderly people but it can cause problems in young people as well in a form of a psychogenic dysphagia.
• Symptoms associated with swallowing problems are coughing, throat clearing, or choking before, during, or after eating or ingesting medicine, and a sensation of an object stuck in the throat (Palmer, J. P. et ai, Am Fam Physician 2000; 61 : 2453- 62).
• a major problem associated with swallowing of small tablets is that the subject does not have an exact feeling where the tablet is located in the mouth so that he/she could coordinate movement of the tongue and muscles of the cheeks to shift the tablet to the right spot and swallow it.
• An analo- gous problem appears when a patient is incapable of coordinating the muscles of cheeks and the tongue.
• Crushing of a tablet or other solid dosage forms of pharmaceuticals and nutritional products may be of help in cases, where the dosage form allows crushing.
• the bad taste of most drugs often prevents most people, let alone those suffering from swallowing difficulties, from taking crushed tablets.
• most solid dosage forms of pharmaceuticals designed for retarded release cannot be crushed without loosing the property of retarded release.
• Swallowing aids in a form of a spray (Pill Glide Spray, FLA- VORx, USA) or a swallowing cup (ORALFLO, Oralflo Technologies, USA) are on the market to help a patient in swallowing problems.
• a solid product that is aimed to facilitate swallowing of tablets and capsules (MedCoat®, Med Coat AB, Sweden).
• the product is comprised of a film that is wrapped around tablet. The film becomes slippery when it is moistened in the mouth, which is thought to aid the swallowing process.
• This system does not, however, soften the touch of hard tablet against the palate of the mouth, and therefore it does eliminate the unpleasant feeling some people experience during swallowing of tablets.
• the slippery film does not act as an active transporter that carries the tablet to the trigger zone of the swallowing reflex.
• wrapping of a film around a tablet may be a troublesome task for elderly people, since it requires handy fingers.
• the tablets and capsules may still need drinking water while being ingested.
• US Patent No. 6337083 B1 describes an oral delivery method and a composition for solid medications or dietary supplements in which swallowing of solid objects, e.g., tablets and capsules, are aided by additives mixed with a base liquid.
• a base liquid usually water or juice.
• This prior art oral delivery composition is bottled in liquid form or prepared from dry substances immediately before use by adding the base liquid.
• WO2007/0351 17 A1 describes another oral vehicle for systemic pharmaceuticals comprising a semi-solid agar gel bolus that contains dispersed active pharmaceutical ingredients in various forms, such as grains and coated grains (microcapsules). The active ingredients are released when the bolus is disrupted in the mouth.
• EP 0651997 B1 describes preparations of capsule-free boluses made of agar for use in the administration of drugs through the buccal cavity. These boluses are hard enough to withstand being pushed through a blister pack. The active pharmaceutical ingredients are suspended in the described boluses that are meant to be disintegrated in the buccal cavity.
• WO2004/037231 A1 describes capsule preparations for medicinal use wherein the film-forming composition of the capsule shell contains gum arabic and a water-soluble polymer. These capsule shells have good me- chanical strength and low brittleness and they can contain pharmaceutical agents as fill material.
• EP 0389700 A1 describes capsules which include a plurality of soft agar-walled microcapsules prepared by dropping method. Some characteristics of the capsule film in these capsules, such as water solubility and heat resistance, differ from those of soft capsules made from gelatin base material.
• EP 0950402 B1 describes a chewable pharmaceutical with a gelatin matrix capable of being rapidly and easily swallowed.
• the gelatin matrix contains dispersed active pharmaceutical ingredients as a ready-made preparation.
• WO2004/067041 A1 discloses formulations of semi-solid non-encapsulated beads for delivering toothpaste into the mouth and breaking up rapidly under applied force. These beads are not intended to be swallowed. Active ingredients are finely dispersed or dissolved in the beads.
• the present invention addresses to widely occurring swallowing problems by providing new means and methods for facilitating the oral administration of solid forms of pharmaceutical and nutritional products.
• An object of the present invention is to provide a swallowing aid, which serves both as a storage package and an applicator means of an oral vehicle which in turn consists of a semi-solid bolus and a lubricating liquid, for carrying the solid objects.
• the swallowing aid contains an oral vehicle to facilitate swallowing of solid dosage forms of pharmaceuticals or nutritional products in humans.
• the semi-solid bolus carries these products during a swallowing process and also makes the contact of solid dosage forms with the mouth softer.
• the present invention provides a new kind of an oral vehicle together with a delivery or applicator device and a method whereby swallowing solid pharmaceutical and nutritional products becomes easier and, in utmost cases, even becomes possible for subjects suffering from swallowing problems.
• the invention further provides a new type of an applicator means for a semi-solid bolus that works both as an applicator and a storage for the bolus.
• the present invention relates to a swallowing aid for administering a solid product, said swallowing aid comprising an oral vehicle comprising
• a semi-solid bolus prepared from a non-flowing base material which is a synthetic or natural dispersion system selected from the group consisting of gels, pastes, oil-in-water emulsions, water-in-oil emulsions, natural substances, and mixtures of two or more of such colloidal dispersions, the viscosity of the dispersion system being higher than 10 000 centipoise (mPa-s) at 20°C as measured by a filament stretching extensional rheometer, and
• a lubricating non-viscous liquid surrounding the bolus the lubricating liquid being comprised of a freely-flowing fluid selected from a group consisting of water, a vegetable oil or an oil-in-water emulsion, wherein the lubricating liquid is present in an amount of 0.05 ml to 100 ml, and
• an applicator means in a form of a container, a plastic vial or a plastic tube.
• the present invention further relates to the use of the swallowing aid for administering solid forms of pharmaceutical and nutritional products.
• Figure 1 shows examples of alternative ways for manufacturing of tube blisters.
• Figure 2 shows an example of a tube blister set/assembly.
• Figure 3 shows examples of different dimensions and shapes of tube blisters of the invention.
• Figure 4 illustrates the method of use of a ready-filled tube blister of the present invention for the administration of a tablet or a capsule.
• Figure 5 illustrates the function of one embodiment of the swallowing aid of the invention. Detailed description of the invention
• the present invention relates to a swallowing aid for a solid pharmaceutical or nutritional product.
• the swallowing aid of the present invention contains an oral vehicle based on a non-flowing dispersion system, such as gel, paste, oil-in-water emulsion or a water-in-oil emulsion, formed to a semi-solid bolus, which can, to a large extent, maintain its shape.
• the semi-solid bolus of the invention is surrounded by a lubricating liquid, which allows a free sliding of the bolus from its applicator.
• the bolus of the present invention shows a semi-solid texture and characteristics which allow it to maintain its shape in the absence of any supporting vial.
• bolus refers to a preparation having a shape of a cylinder, cut cone, enlongated oval, rounded triangle, polygon, and like, prepared from a non-flowing material as described below.
• the bolus is also characterized in that its internal cohesion forces maintain the bolus mass as a unity even in the situation when considerable high external forces change the bolus shape.
• the term "semi-solid” refers to a highly viscous consistency of preparations that contain a simple or compound base, in which one or more substances are dissolved or dispersed.
• the viscosity of the bolus base of the oral delivery devise of the present invention is higher than 10 000 centipoise (mPa-s) at 20°C, preferentially 100 000 to 2 000 000 centipoise, as measured by a filament stretching extensional rheometer.
• the dispersion system used to prepare the bolus of the invention is a gel, paste, oil-in-water emulsion or water-in-oil emulsion, preferably an oil-in-water emulsion. It may also be a mixture of two or more of these colloidal dispersions. Alternatively, these colloidal dispersions may also form layers on each other or they can surround each other as a shell.
• the bolus prepared especially of sugars and/or proteins may also possess a construction of foam (see below). Preferably, the bolus is composed of separate pure constituents described below.
• the final bolus may preferably also be prepared of natural substances, such as a specifically treated vegetable, animal fat and meat and also of dairy products, by adjusting the viscosity of the final bolus to show semi-solid texture and characteristics, which allows to maintain the shape of the bolus in the absence of any supporting vial.
• it can be prepared of a mixture of pure colloidal dispersion systems and natural products.
• Gels and pastes as two subgroups of these dispersion systems play the most important role in the present invention, since by virtue of their structure they are easily deformed by an applied force, yet generally retain a predetermined shape on removal of the force unless deformation exceeds a limit. The force of gravity is less than the limit, and therefore while standing without any supporting vial the shape is maintained.
• Gels consist of liquids gelled by means of suitable gelling agents thereby creating a non-flowing, adhesive mass which exhibits strong cohesive forces but has a low shear strength.
• the molecular structure of a gel consists of a framework of long, variably cross-linked or tangled filaments of a gelling agent for supporting or containing other molecules.
• Hydrophilic gels are preparations of a water miscible liquid medium, such as water, buffer solutions, glycerol or propylene glycol, gelled with a suitable gelling agent.
• Lipophilic gels are, for instance, preparations of, e.g., fatty oils gelled with colloidal silica or aluminum soaps.
• the gelling agents are polysaccharides or other polymeric compounds. Suitable gelling agents include starches, vegetable gums, proteins, cellulose derivatives, carbomers, poloxamers and magnesium- aluminium silicates. Specific examples of gelling agents include but are not limited to: cellulose ethers, guar, guar derivatives, locust bean gum, psyllium, gum arabic, gum tragacanth, carrageenan, agar, algin, xanthan, schleroglu- can, dextran, pectin, starch, chitin, and chitosan. Animal-originated gelling agents include gelatin, prepared from collagen extract, egg white, and like.
• Naturally occurring seaweed provides gels with a structure based on polysaccharide chains including polymers of D-mannuronic acid or L-guluronic acid (examples include alginic acid and its salts), or sulphated galactans (examples include agar, porphyran, furcellaran, and kappa-, iota- and gamma- carrageenan), or combinations, analogues or derivatives thereof.
• food grade structural gels comprise mixtures including one or more of: gelatin, agar, carrageenan, locust bean gum, guar gum (guaran), pectin, alginates, cellulose derivatives (e.g., carboxy methyl cellulose) and starches.
• Preferred gels and gelling agents used for the preparation of the semi-solid bolus of the invention are alginates and cellulose derivatives.
• alginates are used as gels and gelling agents in combination with calcium ions. It is known that calcium adheres to alginate gel structure and strengthens the gel. This is preferred, where fast disruption of the bolus is desired. In stomach, the protons of the gastric juice replace calcium from the bolus structure and induce an efficient disruption of the bolus. Additionally, the bolus can be prepared using a smaller amount of alginates. Although binding of magnesium ions to alginate is weaker than that of calcium ions, magnesium salts can be used in an analogous way, since their affinity for alginate is higher than that of sodium ions and since the binding of magnesium ions is abolished below pH 3.
• Pastes are semi-solid preparations containing large proportions, e.g., 5 to 60 percent, preferably 20 to 30 percent, of solids finely dispersed in the base.
• the paste base is usually a liquid medium, such as water, a buffer solution, glycerol or propylene glycol, however, contained in a smaller amount than in a gel.
• the solid substances in a paste include pieces of any parts of plants (e.g., vegetables and herbs), and water- insoluble substances (e.g., cellulose) extracted from plants.
• the contents of various substances in a bolus are adjusted so that the bolus maintains 40 to 100 percent of its shape after sliding out from the applicator means, such as a tube blister.
• the extent of maintaining the shape is determined by measuring the maximum height of the bolus on the horizontal plane and by comparing this height to the opening diameter of the tube blister.
• the content of gelling agents in boluses varies between 1 and 10 percent, a preferred amount being 3 to 6 percent (e.g., for alginate) and 1 to 5 percent (e.g., for hydroxypropyl methylcellulose).
• the amount of pure calcium is 0.1 to 10 percent (w/w) and preferentially 0.3 to 1 percent of the amount of alginate.
• an oil-in- water emulsion is one of the constituents of the bolus
• the content of a vegetable oil used in its preparation varies between 5 and 30 percent (expressed as percent of bolus weight), a preferred amount being 7 to 15 percent, and in the case of a water-in-oil emulsion the oil content is between 55 to 90 percent, a preferred amount being 60 to 70 percent.
• the emulsifier content is adjusted according to the amount of the internal phase of the emulsion and may be 1 to 10 percent of that amount, preferably 3 to 6 percent.
• the emulsifiers suitable for oil-in-water emulsions are substances with the HLB value between 8 and 18, such as sorbitan mono- laurate, polyoxyethylene lauryl ether, polyoxyethylene monostearate, triethano- lamine oleate, polyoxyethylene sorbitan mono-laurate, -oleate, -palmitate, polyoxyethylene lauryl ether, and polyoxyethylene monostearate.
• the emulsifiers suitable for water-in-oil emulsions are substances with the HLB value between 4 and 6, such as sorbitan mono-oleate, -stearate, -pamitate, and propylene glycol monolaurate.
• the different kind of emulsifiers can also be blended to obtain the desired HLB value both for water-in-oil and oil-in water emulsions.
• the solid material in pastes may additionally include various fibers in order to treat constipation in patients bound to bed. Poorly digestible plant fibers included in the formulation of boluses stimulate the intestinal motility and therefore provide additional functional benefits in subjects suffering from constipation.
• Water- insoluble microcrystalline cellulose serves as an example of a fiber also for this purpose.
• Other suitable fibers include Psyllium fibers and Flax Seed fibers.
• the content of water-insoluble fibers is between 5 and 60 percent, preferably 20 to 30 percent.
• the paste may contain lactic acid bacteria to help in keeping the gastro-intestinal function normal. This is beneficial especially, when the oral vehicle of the present invention is used to facilitate the swallowing of antibiotics.
• the base may consist of natural or synthetic substances and may be composed of single phase or multiphase texture. According to the nature of the base, the preparations may have hydrophilic or hydrophobic properties.
• Food additives possessing desired odor may be used as flavoring agents to increase the compliance of humans and animals to ingest the oral vehicle of present invention.
• the ingestion is made more pleasant for instance by adding a synthetic flavor substance to the bolus material and/or to the lubricating liquid.
• the compound 1 -p-menthene-8-thiol possesses odor of a tropical fruit and is therefore a suitable flavoring agent.
• the taste and also the color of the bolus can be modified by various extracts of berries (e.g., Blackcurrant Extract (E 163)) and fruits (e.g., organic apple flavor).
• These kinds of flavors are examples of suitable substances for humans and herbivorous animals.
• the odor of meat and roast for carnivores is obtained for instance by adding a desired amount of 3-(methylthio)propanol or 2-methyl-3- tetrahydrofuranthiol to the bolus.
• sweeteners such as various natural sugars and sugar alcohols, e.g., saccharide, sorbitol, xylitol, and/or sweet- tasting synthetic compounds (intense sweeteners), e.g., saccharin, cyclamate, aspartame, acesulfame K, sucralose and like, to the base of the bolus and/or to the lubricating liquid.
• sweeteners such as various natural sugars and sugar alcohols, e.g., saccharide, sorbitol, xylitol, and/or sweet- tasting synthetic compounds (intense sweeteners), e.g., saccharin, cyclamate, aspartame, acesulfame K, sucralose and like
• coloring agents e.g., those suitable for use in foods, such as artificial coloring agents (Sunset Yellow FCF (Orange shade), Brilliant Blue FCF, Allura Red AC and like) and natural coloring agents (caramel coloring, betanin and like), can be added to the base of the bolus and/or to the lubricating liquid.
• artificial coloring agents Sunset Yellow FCF (Orange shade), Brilliant Blue FCF, Allura Red AC and like
• natural coloring agents caramel coloring, betanin and like
• Flavoring agents, sweeteners and coloring agents are added as much as is sufficient, usually 1 to 30 ppm for flavoring agents, 1 to 5 percent for sweeteners, 0.001 to 0.01 percent for intense sweeteners, and 0.001 to 0.5 percent for coloring agents.
• preservatives e.g., parabens, such as methylparaben, ethylparaben and propylparaben
• sorbic acid and its salts such as potassium and calcium sorbate
• benzoic acid and its salts such as sodium-, potassium and calcium benzoate, and like
• Preservatives are used at the level of 0.1 to 0.3 percent.
• the bolus is surrounded by a freely flowing lubricating liquid. It facilitates the sliding of the bolus out of the applicator means, such as a tube blister, into which it is packed, into the mouth and finally down to the throat.
• the lubricating liquid is a non-viscous liquid, for instance water, a vegetable oil containing only a minor amount (e.g., ⁇ 1 %) of free fatty acids, such as sunflower oil, corn oil and rapeseed oil, a mixture of water with a vegetable oil and an emulsifier, such as polysorbate derivative, providing an oil-in-water emulsion, a dairy product in form of an oil-in-water emulsion, such as cream, diluted yogurt and whole milk.
• a non-viscous liquid for instance water, a vegetable oil containing only a minor amount (e.g., ⁇ 1 %) of free fatty acids, such as sunflower oil, corn oil and rapeseed oil, a mixture of water with a vegetable oil and an emulsifier, such as polysorbate derivative, providing an oil-in-water emulsion, a dairy product in form of an oil-in-water emulsion, such as cream, diluted yogurt and whole milk.
• the volume of the lubricating liquid is determined by the size of the applicator means, such as a tube blister, and it varies from the minimum amount necessary to moisture the surface of bolus (for instance, 0.05 to 0.5 ml) to 20 ml and 100 ml of liquid in oral vehicle for humans and larger animals, respectively.
• the volume of the lubricating liquid is preferably 0.5 to 10 ml, more preferably 1 to 10 ml, and most preferably 1 to 5 ml.
• oral vehicle refers to the semi-solid bolus of the present invention together with the lubricating liquid.
• the former is used to carry solid objects whereas the latter facilitates sliding of bolus.
• the oral vehicle of the present invention serves as a carrier of solid dosage forms.
• the dosage forms of pharmaceuticals and nutritional product are carried intact through the mouth and are not intended to release nor do they release the active ingredients in the mouth while they are carried by the bolus of the present invention.
• the oral vehicle of the present invention dissolves rapidly in the gastric juice, as illustrated in Fig. 5.
• the absorption of, for instance, tablets or capsules is not delayed.
• boluses containing an oil-in-water emulsion start disrupting in seconds in the stomach.
• the oil-in-water emulsion of the bolus dilutes when coming into the contact with the gastric juice, the bolus structure becomes porous, the contact surface between the bolus material and the gastric juice increases, and the bolus disrupts rapidly-
• the solid dosage form such as a tablet or a capsule, is placed into the tip of the non-flowing gel or paste bolus of the invention.
• the semi-solid structure allows the tablet or capsule to be inserted into the gel and become buried into it.
• the tip of the bolus may contain an opening like a cut, a groove or a hole, where the tablet or capsule is inserted. Due to the semi-solid structure of the bolus, the tablet or the capsule will be entirely surrounded by the bolus material. This, in addition to aiding the swallowing, also masks the possible unpleasant taste of the tablet or capsule.
• the oral vehicle of the present invention is loaded with solid dosage forms of pharmaceutical or nutritional products (e.g., tablets and capsules) just before the use.
• active pharmaceutical and nutritional ingredients are administered intact in their nor- mal dosage forms without a direct contact of the active ingredients with the matrix of the bolus.
• the oral vehicle of the invention essentially differs from prior art preparations, such as those described in WO2007/0351 17, EP 0651997 B1 , WO2004/037231 and EP 0950402 B1 , which contain the active agents dispersed or suspended within.
• the oral vehicles of the invention which have the same size and diameter, can be used for the administration of several different solid pharmaceutical or nutritional products the subject may be taking, such as medication for hypertension, high cholesterol, painkillers and like, provided that the sizes of the tablets are similar.
• a patient having several daily medications need only one size or only two or three different sizes of the swallowing aid of the present invention.
• the oral vehicle of the present invention makes it possible to ingest two or more tablets simultaneously.
• the form of the semi-solid bolus of the present invention is preferably cylinder-shape or nearly cylinder-shape, such as cut-cone shape.
• the semi-solid bolus may be mounted (casted) into any suitable shape, such as an oval shape, a rounded triangle or rounded polygon.
• the selection of an ideal diameter of the bolus for a particular use depends, in addition to anatomical factors, on the size of tablet or capsule to be ingested or administered.
• the diameter of the bolus should be at least 2 mm, for instance 2.5 mm or 3 mm, larger than that of the tablet or capsule in order to properly bury these solid products in the tip of the bolus.
• the diameter of a cylinder-shape or nearly cylinder-shape bolus is usually between 5 to 50 mm. Especially for use in humans, the diameter of the bolus is preferably from 6 to 12 mm for children and from 10 to 20 mm for adults. In veterinary use, the optimal diameter is between 6 and 12 mm for small pets, between 10 and 20 mm for large pets and small domestic animals, and between 20 and 40 mm for large domestic animals.
• the length of a semi-solid bolus may vary from 2 cm to 20 cm.
• the first issue is the anatomical distance from the site, where the tube blister touches the lips, to the site in the mouth, where the trigger zone for swallowing reflex is located.
• the second issue is the requirement that the bolus must be long enough so that it does not easily turn transversely in the mouth. In this way, it is guaranteed that the tablet or capsule pressed into the tip of bolus reaches the trigger zone of swallowing.
• the "excess" mass of the gel or paste with respect to the tablet of capsule does not cause any harm although it may require extra swallowing. This is because the large mass of the bolus aids the tablet or capsule to slide down the throat.
• the following lengths are preferred for the boluses: in humans, 20 to 30 mm for children and 30 to 60 mm for adults; in animals, 20 to 30 mm for small pets, 30 to 60 mm for large pets and small domestic animals, and 100 to 200 mm for large domestic animals. These lengths equal with the corresponding dimensions of the cylinder-shape or cut-cone shape part of applicator means, such as tube blisters.
• the entire length of the applicator means is preferentially 10 to 30 mm longer than the length of the bolus, due to the space reserved for the lubricating liquid in the bottom of the applicator means.
• the bolus is surrounded by a liquid or liquid film between the semi-solid bolus and the applicator means, such as a tube blister.
• the bolus material with relatively poor sliding properties is packed, for instance, in a tube blister having a bottom part suitable for a larger volume of the lubricating liquid.
• the applicator means has in practice the same diameter with the bolus (see text above).
• the length of the applicator means may be somewhat different. Depending on how slippery the surface of the bolus is there may be a need to use various amounts of the lubricating liquid. In the case of insufficient sliding properties a larger space in the bottom of the applicator means is reserved for lubricating liquid. This requires an extension in the length of the applicator means roughly by 10 to 30 mm compared to the length of the bolus. In some cases it is necessary to effectively push the bolus throughout the entire cylinder-shape part of the applicator means.
• the bottom is shaped to form almost a ball, the volume of which maximally equals to the rest of the applicator means.
• the cylinder part of the applicator means may be modified so that the tube opening is slightly wider than the diameter of at the site close to the bottom. This model of the applicator means has then the shape of a cut- cone.
• the applicator means of the swallowing aid of the present invention is a container, a plastic vial or a plastic tube for holding and storing the oral vehicle.
• a preferred applicator means is a tube blister.
• the tube blisters are made of a thin, preferably 0.150 to 0.300 mm, polymer sheet.
• the polymer may be a polyvinyl chloride (PVC), polyethylene (PE) or polypropylene (PP) polymer, which polymers are durable enough to stay unbreakable, when the bottom of tube blister is squeezed to force the bolus to slide out of blister.
• PVC polyvinyl chloride
• PE polyethylene
• PP polypropylene
• PCTFE Polychlorotrifluoro ethylene
• Duplex structures such as PVC/PCTFE, and triplex laminates, such as PVC/PE/PCTFE, may also be used.
• Cyclic olefin copolymers (COC) or polymers (COP) also provide a moisture barrier to blister packs, typically in multilayered combinations with PP, PE, or glycol-modified polyethylene terephthalate.
• the grade of polymers should fulfill the specifications set for product materials in food and/or pharmaceutical industry.
• the thickness of the laminate(s) should be between 0.015 and 0.100 mm.
• the tube blisters are prepared from a plastic polymer sheet by thermoforming utilizing a large pressure and/or physical force to line the moulds of the desired shape.
• the edge of the opening of tube blister is made smooth by bending polymer sheet over a round edge of the mould or by joining a separate smooth ring to the edge of tube blister.
• the cooled blisters are then filled with the oral vehicle and immediately sealed with aluminum foil or plastic film in a heat-sealer.
• the blister technology is preferred in the manufacturing of the desired vial (tubes) for the oral vehicle of present invention but optionally the tubes with similar dimensions and materials can also be prepared individually, e.g., by injection molding machine.
• Another preferred applicator means of the invention is a sachet made of plastic, i.e., of polymers described for the tube blister, or of aluminium film, or of liquid-resistant paperboard.
• the applicator means may be prepared from a liquid- resistant paperboard laminated with one or more of the following polymers: PE, PP, PCTFE, COC, COP and glycol-modified polyethylene terephthalate.
• This type of an applicator means may be manufactured using technology suitable for such liquid-resistant paperboard well known in the art.
• the obtained sachet may have three or more plains in the construction of walls and the cross-section of sachet may have one of the following geometry: triangle, square, pentagon, hexagon, heptagon, and octagon.
• the bottom construction in this type of a sachet is flat.
• the opening of the sachet is lined/sealed with separate smooth edge made of plastic polymer.
• This type of a sachet is characterized also in that it is sealed with aluminum foil or polymer film in an analogous manner with tube blisters. Then the shape of the sachet also determines the shape of bolus to be of a similar pattern.
• the dimensions and shapes of the tube blisters and sachets may vary depending on whether they are used for facilitating intake of solid objects (tablets, capsules) in human or in animal medication.
• Figure 3 illustrates different tube blister models. The sliding of the bolus packed into the cylinder part of a tube blister is aided by the lubricating liquid placed into the bottom part of the tube blister.
• the bottom may have a ball-shape (c, f, g, h, I, j, k, I) or a cone-shape (a, b, d, e) form, and the volume of the bottom part maximally equals with the rest of the same tube (g, j).
• the opening of the tube blister may be one to two millimeters wider than the diameter of the cylinder part at the other end of the tube close to the bottom part.
• This shape is actually a cut section of cone (b, e, h, k) and it facilitates the sliding of the gel or paste bolus out of the tube blister.
• the tube has a narrower part between the cylinder and bottom parts (i, I). This aids separating the bolus from the lubricating liquid, if necessary. Note that the dimensions of the drawn exemplary tube blister models are not exactly in a correct proportional scale.
• the preferred tube blister model that favors the sliding of bolus out of the blister has a round ball-shape bottom the volume of which maximally equals with the rest of the same tube blister.
• the radius of the ball-shape bottom is 12 mm ( Figure 3g and 3j).
• This shape of the tube blister offers also an opportunity to get a good grip on the tube blister.
• Additional facilitation of sliding is achieved with the model in which the opening of the cylinder part of the tube blister is slightly wider (1 to 2 mm) than the diameter of the cylinder part at the site close to the bottom ( Figure 3). This shape of a cut-cone makes it possible that merely a small forward shift of the bolus detaches most part of its surface from the inner surface of the tube blister, which decreases the friction at the interface of the bolus and the tube blister.
• the present invention provides means and methods to facilitate swallowing of solid dosage forms of pharmaceuticals or nutritional products in humans by providing a semi-solid bolus material, packed in a tube blister containing a lubricating liquid, which carries these product forms during swallowing process and also makes the contact of solid dosage forms with the mouth softer.
• the oral administration of tablets and capsules to animals are aided by utilizing the present invention adjusted for herbivorous and carnivorous animals according to the size of animal.
• the invention provides also a new type of blister package for the semi-solid soft bolus that works also as an applicator of bolus directly into the mouth.
• a simple manufacturing method is provided to produce the whole product in an economical way.
• the method of delivering a bolus possessing specific dimensions rapidly out of a tube blister directly into the mouth is based on the following factors: 1 ) the walls of the bottom of the tube blister are thin and flexible; 2) the size of the tube blister is big enough to contain a desired, sufficient volume of lubricating liquid in the bottom of tube blister; and 3) the edge of the blister opening is smooth which allows putting the tube blister in touch with the lips.
• the sealing foil is detached form the tube blister
• the solid object e.g., a tablet or capsule
• the tube blister is lifted between the lips and the bolus is forced to slide out of the blister into the mouth by squeezing the bottom of tube.
• the bolus and/or the lubricating liquid gently come into contact with the trigger zone of the swallowing reflex, the bolus with the buried solid object is swallowed down the throat. The process is markedly facilitated if a subject lifts up his/her chin as much as possible while pouring the oral vehicle from the tube blister into the mouth.
• the present invention provides an oral vehicle comprised of a semi-solid bolus, a lubricating liquid and flavoring and/or coloring agents packed in a tube blister.
• the soft semi-solid base of the bolus is capable of carrying inside its tip a solid object, such as tablet and capsule.
• the bolus aids in swallowing of these oral dosage forms of drugs without causing a danger of inhaling liquid or other material, as often may be the case when tablets are ingested with excessive drinking water.
• a relatively small amount of a lubricating liquid in tube blister facilitates the sliding of bolus.
• the compliance to ingest oral vehicle is stimulated by specific flavoring agents, some of them suitable for humans and carnivorous animals and others for humans and herbivorous animals.
• specific flavoring agents some of them suitable for humans and carnivorous animals and others for humans and herbivorous animals.
• the beneficial microbes and poorly water-soluble plant fiber that may be added to the base of bolus help maintaining normal function of the gastro-intestinal tract.
• the invention provides also a method for manufacturing tube blisters with smooth edge in the opening part (Fig. 1 ).
• Such tube blisters allow the contact of the blister with the lips without a danger of cutting the tissue with shape edges.
• the preferred models of tube blisters are constructed of a ball- shape bottom part for containing a lubricating liquid and a cylinder part for containing the bolus, the dimensions of which match with anatomical measures of a human and animal mouth and also with the size of conventional tablets and capsules (Fig. 3).
• the opening of cylinder part is one to two millimeters wider that the diameter of cylinder part at the site close to the bottom ball actually giving a shape of a cut section of cone (Fig. 3). This further aids the sliding of bolus out of the tube blister, since in this case the initial shift of the bolus detaches most of its surface from the inner surface of the tube blister.
• the combination of various factors of the present invention provides also a method for use of a tube blister.
• One of the three key factors in this method is a thin and flexible wall in the bottom of the tube blister that makes it possible to squeeze the bottom and in this way to force the lubricating liquid move forward to push the bolus forward.
• Another factor is the smooth edge around the opening of tube blister that allows touching of the blister with the lips.
• the third factor is the lubricating liquid that makes the bolus to slide rapidly. Due to these three factors the method facilitates the administration of solid dosage forms of drugs directly from tube blister into the mouth in an efficient manner (Figure 4).
• the present invention relates to a method of use of a swallowing aid of the invention, the method comprising
• Methylparaben is dissolved in 50 ml water (20°C). Sodium alginate and calcium citrate are mixed together as dry substances and then dispersed in the methylparaben solution. Hydroxypropyl methylcellulose is wet- ted and dispersed in 40 ml water (50°C). Subsequently, the obtained dispersion is mixed with the first dispersion containing the other constituents. The mass of the obtained highly viscous gel is set to 100 g with water (20°C).
• Example 3 Mixture of a gel with oil-in-water emulsion
• Methylparaben and calcium citrate are dissolved in 80 ml water and kept at 55°C. Sodium alginate is then wetted with a small amount of water and dispersed in this solution. Sunflower oil is heated to 55°C and mixed with Polysorbate 60 and then added in and thoroughly stirred with the aqueous mixture containing other constituents. The process is continued while adjusting the mass of preparation to 100 g by water.
• Example 4 Mixture of two gels with oil-in-water emulsion
• Methylparaben is dissolved in 40 ml water (55°C). Sodium alginate and calcium citrate are mixed together as dry substances and then dispersed in the methylparaben solution. Hydroxypropyl methylcellulose is wetted in a small amount of water and then dispersed in 40 ml water (55°C). The obtained two dispersions are then combined. Sunflower oil is heated to 55°C and mixed with Polysorbate 60 and then added in and thoroughly stirred with the mixture of aqueous dispersions containing other constituents. The stirring is continued while adjusting the mass of preparation to 100 g by water.
• Example 5 Mixture of a gel with water-insoluble fibers
• Methylparaben is dissolved in 60 ml water and kept at 55°C. Hydroxypropyl methylcellulose is then wetted in small amount of water and dispersed in this solution to obtain a viscous paste. Finally, microcrystalline cellulose and xylitol are mixed with the paste and the mass of preparation is adjusted to 100 g by adding water.
• Example 6 Mixture of a gel with water-insoluble fibers
• Hydroxypropyl methylcellulose 1 .0 g
• Distilled water ad 100 g 100 g
• Methylparaben is dissolved in 30 ml water (20°C).
• Sodium alginate and calcium citrate are mixed together as dry substances and then dispersed in methylparaben solution.
• Hydroxypropyl methylcellulose is wetted in small amount of water and dispersed in 30 ml water (50°C).
• the obtained dispersion is mixed with the first dispersion containing the other constituents except microcrystalline cellulose.
• microcrystalline cellulose is added to the combined dispersions by vigorously mixing throughout the process.
• the mass of the obtained preparation is set to 100 g with water (20°C).
• Example 8 Mixture of a gel with an oil-in-water emulsion and water- insoluble fibers
• Methylparaben is dissolved in 50 ml water and kept at 55°C. Hydroxypropyl methylcellulose is then wetted with a small amount of water and dispersed in this solution. Corn oil is heated to 55°C and mixed with Polysorbate 60 and 3-(methylthio)propanol, and then added in and thoroughly stirred with the aqueous mixture containing other constituents except microcrystalline cellulose. Next, microcrystalline cellulose is added to the combined mixtures by vigorously stirring throughout the process. The mass of the obtained preparation is set to 100 g with water (55°C).
• Example 9 Mixture of a gel with an oil-in-water emulsion and water- insoluble fibers
• Example 10 Mixture of two gels with an oil-in-water emulsion and water- insoluble fibers
• Hydroxypropyl methylcellulose 1 .0 g
• Methylparaben is dissolved in 25 ml water (55°C). Sodium alginate and calcium citrate are mixed together as dry substances and then dispersed in methylparaben solution. Hydroxypropyl methylcellulose is wetted in a small amount of water and then dispersed in 25 ml water (55°C). The obtained two dispersions are then combined. Sunflower oil is heated to 55°C and mixed with Polysorbate 60 and then added in and thoroughly stirred with the mixture of aqueous dispersions containing other constituents except micro- crystalline cellulose. Next, microcrystalline cellulose is added to the combined mixtures by vigorously stirring throughout the process. The mass of the obtained preparation is set to 100 g with water (55°C).
• Example 11 Manufacturing of tube blisters with a smooth edge
• the moulds providing a blister shape of a normal test tube is presented as an example of thermoforming of tube blisters of the present invention from plastic polymer sheet (Figure 1A).
• Figure 1A plastic polymer sheet
• a separate smooth plastic ring is heat-sealed to the edge of the cylinder-shape part of the blister ( Figure 1 B) after cutting the blister free from the plastic sheet.
• the smooth edge is created by bending the heated plastic sheet so that the cutting site (cut by melting) is not at the edge of tube blister but, e.g., 20 mm apart ( Figure 1 C).
• This is the preferred model from the manufacturing point of view, whereas the model with the plastic ring is more convenient to handle.
• the smooth edge of the tube blister eliminates all possibilities to damage the lips while emptying the bolus from tube blister into the mouth.
• the cooled blisters are filled with an oral vehicle of the present invention and immediately sealed with aluminum foil or plastic film in heat- sealer.
• a bolus material with relatively poor sliding properties is packed in a tube blister with a bottom part for larger volume of lubricating liquid.
• a set or an assembly of filled tube blisters is shown in Figure 2.
• Example 12 Method for use of a tube blister

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• 2010
  • 2010-03-19 FI FI20105278A patent/FI123712B/fi not_active IP Right Cessation
• 2011
  • 2011-03-16 WO PCT/FI2011/050224 patent/WO2011114002A1/en not_active Ceased

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